While our understanding of the natural history of childhood wheezing is still evolving, epidemiological studies have characterized distinct patterns of wheezing based on age of onset, remission, and persistence with further classification based on allergic, immunologic and physiological parameters. These wheezing phenotypes, in turn, have been differentially associated with lung function changes, including airway resistance. Exposure to environmental toxins during critical periods of prenatal and/or postnatal development may alter risk for developing wheezing phenotypes and alter the normal course of lung morphogenesis and maturation, potentially impacting both structure and function of the respiratory system. Moreover, when normal development is altered, the early effects may persist into adult life, magnifying the potential public health impact. Aberrant or excessive local and systemic immune responses, both innate and adaptive, may be a central determinant. Thus, identifying specific programming agents that help to shape the functional competence of the immune system and interrelated systems during this period may give new insights into the mechanisms by which they exert their effects. Emerging evidence that psychological factors (i.e., stress) influence neuroendocrine and immune processes suggest their possible role in wheeze expression and lung growth and development. We propose that stress-elicited disruption of interrelated systems - neuroendocrine, autonomic, and immune - during perinatal development may lead to increased vulnerability to wheezing respiratory illnesses and altered lung function in later childhood. Conceived under an economies-of-scale model, this competitive renewal takes advantage of an existing NIH funded prospective pregnancy cohort (R01 HL080674, RJ Wright, PI) of urban mother-child pairs with intensive assessment of prenatal and early maternal caregiving stress including biomarkers of stress-reactivity in mothers and children already in an existing database, and proposes new data collection at age 6 years to more definitively characterize wheezing phenotypes and lung function characteristics previously linked to later life morbidity. We will prospectively examine the influence of perinatal maternal stress on risk for childhood wheezing phenotypes (early, late onset, persistent) and lung function outcomes [spirometry, airway inflammation (e.g., eNO), airway impedance in response to a social stressor] at age 6 years. We will also explore potential interrelated underlying mechanisms operating in the link between perinatal stress and (1) autonomic reactivity; (2) neuroendocrine responses; and (3) immunomodulation assessed through lymphocyte stimulation and cytokine profiles. And finally, we will explore the influence of perinatal stress on epigenetic profiles (pathway specific) which may then predict wheeze phenotypes and subsequent lung function outcomes. PUBLIC HEALTH RELEVANCE: An important step toward identifying children at risk for costly pediatric disorders is the identification of mechanisms that may lead to and maintain early predisposition, especially those that may be amenable to intervention. Early life factors contributing to developmental respiratory outcomes including wheezing phenotypes and lung development are of particular interest given the link between these factors and chronic obstructive pulmonary disease (COPD) in later life. COPD is projected to be the fourth leading cause of death worldwide by 2020. It is highly plausible that susceptibility to asthma/wheeze phenotypes and altered lung function may be linked through stress-elicited disruption in key physiological systems - neuroendocrine, autonomic, immune - albeit direct evidence in humans is lacking. Knowledge gained from the proposed research may inform new pathways linking stress to lung structure-function changes.